Patent IE-35972-B1 (IE)
Title: Phenethyl-aralkylamine compounds and their preparation
IPC: A61K31/135
Filed: 1972-01-11
Abstract: 1355449 Phenethyl-aralkylamine derivatives MERCK & CO Inc 12 Jan 1972 [15 Jan 1971 7 Dec 1971] 1494/72 Heading C2C Novel compounds VII in which X and X<SP>1</SP> may each represent more than one substituent selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 1-5 alkoxy, C 1-4 perfluoroalkoxy, C 1-4 perfluoroalkyl, phenyl, substituted phenyl, C 1-4 acyl, C 1-4 perfluoroacyl, amino, C 1-4 alkylamino, C 2-8 dialkylamino, C 1-4 acylamino C 1-4 perfluoroacylamino, cyano, carboxy, carbamoyl, C 2-5 alkylcarbamoyl, C 3-9 dialkylcarbamoyl, C 2-6 alkoxy carbonyl, mercapto, C 1-6 alkylthio, C 1-4 perfluoroalkylthio, C 1-6 alkylsulphonyl, C 1-4 perfluoroalkylsulphonyl, C 1-4 alkylsulphamoyl or C 2-8 dialkylsulphamoyl; m is 1 to 4; R<SP>0</SP> is methylene and when m is 1 is additionally C 2-5 alkylidene or di-(C 1-4 alkyl)methylene and R 2 and R 3 are hydrogen, C 1-6 alkyl, aralkyl, C 2-6 alkenyl, C 2-6 alkynyl or R 2 is joined to R 3 or to one of the methylene carbon atoms of R<SP>0</SP> to form with the N atom an imidazolinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl or (C 1-5 alkyl)piperazinyl radical with the proviso that if-(R<SP>0</SP>) m -NR 2 R 3 is 2-dimethyl aminomethyl then one of X and X<SP>1</SP> is other than hydrogen, are prepared by (1) reduction of a compound VIII preferably using lithium aluminium hydride, (2) reduction of a compound IX in which R<SP>11</SP> is hydrogen or C 1-5 alkyl, (3) reduction of a compound X and this method may include an homologation procedure involving conversion of the cyano substituent by hydrolysis to carboxyl, reduction with lithium aluminium hydride to -CH 2 OH, halogenation to CH 2 Br and treatment with potassium cyanide to the next higher homologue, (4) reaction of an amine HNR 2 R 3 with a compound XI where Hal is halogen, (5) alkylating (preferably methylating with formaldehyde and formic acid) a compound XII to form the corresponding N-alkyl or N,N-dialkyl compound or (6) hydrolysis of a compound XIII or catalytic hydrogenation of a compound XIV to form a compound I in which (R<SP>0</SP>) m -NR 3 R 4 is the group -CR 3 R 4 -NH 2 in which R 3 and R 4 are C 1-4 alkyl. Methods (4) and (5) are used to produce N,N-dimethyl-2-phenethyl-benzylamine (XVI) a known compound. Preferred compounds are 2-(4-bromophenethyl)-N-methyl-benzylamine; N-methyl-2-phenethylbenzylamine; 2-(4-bromophenethyl)benzylamine; 2-(4-bromophenethyl)- )- N,N-dimethylbenzylamine, 2-(4-bromophenethyl)- phenethylamine; 2-(4-bromophenethyl)-N-methylphenethylamine; α,α-dimethyl-4-phenethylbenzylamine; and method (6) is used to produce compounds in which X and X<SP>1</SP> are fluoro, trifluoromethyl; hydroxy, methyl, ethyl, methoxy, ethoxy, methylthio and methylsulphonyl. Compounds XIII in which X and X<SP>1</SP> are hydrogen are prepared from compounds IIA by forming a Grignard reagent and reacting this with an aliphatic ketone to form a benzyl alcohol which is used in a Ritter reaction with hydrogen cyanide in sulphuric acid. Acetylenic compounds XIV are prepared by reaction of an appropriately substituted cuprous phenyl acetylide and N-formyl-α,α-dialkyl-4-iodo benzylamine. Compounds I and XVI are anti-arrhythmic agents and form with a diluent, carrier or excipient a pharmacetical composition which may be administered orally or parenterally.
[GB1355449A]